Rapid whole-genome sequencing for genetic disease diagnosis in neonatal intensive care units.

Creator(s)

Carol J. Saunders, Children's Mercy HospitalFollow
Neil Andrew Miller, Children's Mercy Hospital
Sarah E. Soden, Children's Mercy HospitalFollow
Darrell Lee Dinwiddie, Children's Mercy Hospital
Aaron Noll, Children's Mercy Hospital
Noor Abu Alnadi, Children's Mercy Hospital
Nevene Andraws, Children's Mercy Hospital
Melanie Patterson, Children's Mercy HospitalFollow
Lisa Ann Krivohlavek, Children's Mercy Hospital
Joel Fellis
Sean Humphray
Peter Saffrey
Zoya Kingsbury
Jacqueline Claire Weir
Jason Betley
Russell James Grocock
Elliott Harrison Margulies
Emily G. Farrow, Children's Mercy HospitalFollow
Michael Artman, Children's Mercy Hospital
Nicole Pauline Safina, Children's Mercy Hospital
Joshua Erin Petrikin, Children's Mercy Hospital
Kevin Peter Hall
Stephen Francis Kingsmore, Children's Mercy Hospital

Document Type

Article

Publication Date

10-3-2012

Identifier

DOI: 10.1126/scitranslmed.3004041; PMCID: PMC4283791

Abstract

Monogenic diseases are frequent causes of neonatal morbidity and mortality, and disease presentations are often undifferentiated at birth. More than 3500 monogenic diseases have been characterized, but clinical testing is available for only some of them and many feature clinical and genetic heterogeneity. Hence, an immense unmet need exists for improved molecular diagnosis in infants. Because disease progression is extremely rapid, albeit heterogeneous, in newborns, molecular diagnoses must occur quickly to be relevant for clinical decision-making. We describe 50-hour differential diagnosis of genetic disorders by whole-genome sequencing (WGS) that features automated bioinformatic analysis and is intended to be a prototype for use in neonatal intensive care units. Retrospective 50-hour WGS identified known molecular diagnoses in two children. Prospective WGS disclosed potential molecular diagnosis of a severe GJB2-related skin disease in one neonate; BRAT1-related lethal neonatal rigidity and multifocal seizure syndrome in another infant; identified BCL9L as a novel, recessive visceral heterotaxy gene (HTX6) in a pedigree; and ruled out known candidate genes in one infant. Sequencing of parents or affected siblings expedited the identification of disease genes in prospective cases. Thus, rapid WGS can potentially broaden and foreshorten differential diagnosis, resulting in fewer empirical treatments and faster progression to genetic and prognostic counseling.

Journal Title

Sci Transl Med

Volume

4

Issue

154

First Page

154

Last Page

154

MeSH Keywords

Connexins; Genetic Diseases, Inborn; Genome, Human; Humans; Infant, Newborn; Intensive Care Units, Neonatal; Retrospective Studies; Sequence Analysis, DNA

Keywords

Connexins; Genetic Diseases, Inborn; Genome, Human; Humans; Infant, Newborn; Intensive Care Units, Neonatal; Retrospective Studies; Sequence Analysis, DNA

Comments

Grant support

• U19 HD077693/HD/NICHD NIH HHS/United States

Recommended Citation

Saunders, C. J., Miller, N., Soden, S. E., Dinwiddie, D., Noll, A., Alnadi, N., Andraws, N., Patterson, M., Krivohlavek, L., Fellis, J., Humphray, S., Saffrey, P., Kingsbury, Z., Weir, J., Betley, J., Grocock, R., Margulies, E., Farrow, E. G., Artman, M., Safina, N. P., Petrikin, J. E., Hall, K. P., Kingsmore, S. F. Rapid whole-genome sequencing for genetic disease diagnosis in neonatal intensive care units. Sci Transl Med 4, 154-154 (2012).